环境致癌物B[a]PDE通过抑制AKT2蛋白诱导支气管上皮细胞恶性转化的机制研究

AKT2是蛋白激酶B的异构体，传统认为其主要通过磷酸化活化后作为癌基因促进肺癌的发生发展，然而其在苯并芘代谢产物B[a]PDE致肺癌发生发展过程中的作用机制尚不明确。我们前期研究发现B[a]PDE暴露促进AKT1表达以及AKT的磷酸化，却显著抑制AKT2蛋白的表达。而过表达AKT2明显的抑制B[a]PDE诱导的COX-2、TNF-α炎症因子表达，以及人支气管上皮细胞恶性转化。据此推测AKT2有别于促进肺癌发生发展的作用，在B[a]PDE诱导人支气管上皮细胞恶性转化过程中发挥着经典激酶功能之外的重要作用，但相关分子机制有待进一步研究。我们拟利用分子生物学及生物信息学技术，在良好的前期基础上探索B[a]PDE通过抑制AKT2表达从而诱导人支气管上皮细胞恶性转化的分子机制。本项目的开展将系统解析AKT2与B[a]PDE致肺癌发生发展的关系，为苯并吡环境暴露下诱导肺癌发生的防治提供一定的理论依据。

AKT2 is an isoform of protein kinase B, acting as an oncogene to promote the development of lung cancer through phosphorylating and activating its substrates. However, its role and mechanism in the development of B[a]PDE-induced lung cancer are still unclear. Our recent study found that B[a]PDE exposure promoted AKT1 expression and AKT phosphorylation, but significantly inhibited AKT2 protein expression. Overexpression of AKT2 significantly decreased the expression of COX-2, TNF-α, and inhibited the malignant transformation of human bronchial epithelial cells which was induced by long-term exposure to B[a]PDE. We speculate that besides of its classical function of kinase, AKT2 may play an important role in the malignant transformation of human bronchial epithelial cells induced by B[a]PDE. It is different from the traditional research results that AKT2 acting as an oncogene in lung cancer. However, the related molecular mechanism needs to be further studied. Based on the good preliminary work, molecular biology and bioinformatics technology will be used in this study to explore the molecular mechanism of B[a]PDE-induced malignant transformation of human bronchial epithelial cells by inhibiting AKT2 protein expression. This project will systematically analyze the relationship between AKT2 and B[a]PDE-induced lung cancer, and provide a theoretical basis for the prevention and treatment of lung cancer which induced by Benzo[a]pyrene exposure in the environment.